LBA-1 RATIONALE-306: Randomized, global, placebo-controlled, double-blind phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC)
Authors: H. Yoon, K. Kato, E. Raymond, R. Hubner, Y. Shu, Y. Pan, Y. Jiang, J. Zhang, S. Park, T. Kojima, C. Lin, E. Gotovkin, L. Wyrwicz, R. Ishihara, L. Li, A. Tao, J. Shi, L. Wang, J. Xu
Journal: Annals of Oncology (2022)

Tislelizumab, an anti-programmed cell death protein 1 antibody, has demonstrated a survival benefit as second-line treatment in ESCC. Here, we report interim analysis (IA) data from the phase 3 RATIONALE-306 study, which evaluated the efficacy and safety of tislelizumab plus chemotherapy vs placebo plus chemotherapy in patients with advanced or metastatic ESCC in the first-line setting. In this randomized, double-blind, global study, adults with unresectable locally advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were enrolled regardless of programmed death-ligand 1 (PD-L1) expression status. Patients were randomized (1:1) to receive tislelizumab 200 mg (Arm A) or placebo (Arm B) intravenously once every three weeks, both in combination with investigator-chosen chemotherapy (ICC; platinum [cisplatin or oxaliplatin] and fluoropyrimidine [capecitabine or 5-FU] or platinum and paclitaxel) until disease progression per RECIST v1.1, intolerable toxicity, or withdrawal. Randomization was stratified by geographic region, prior definitive therapy and ICC. The primary endpoint was overall survival (OS) in the intent-to-treat (ITT) population. Hierarchical sequentially-tested secondary endpoints were progression-free survival (PFS), objective response rate (ORR) by the investigator, OS in the PD-L1 score ≥10% subgroup, and health-related quality of life. Other secondary endpoints included duration of response (DoR) by the investigator, and safety. Of 649 patients enrolled from 16 countries/4 regions (74.9% and 25.1% from Asia and non-Asian countries [Europe, Oceania, and North America]), 326 and 323 patients were randomized to Arms A and B, respectively (ITT population). At data cutoff (28/02/2022), median follow-up was 16.3 and 9.8 months in Arms A and B, respectively. The study met its primary endpoint at IA by demonstrating statistically significant improvement in OS in Arm A vs Arm B (median OS: 17.3 vs 10.6 months; HR 0.66 [95% CI 0.54, 0.80], p<0.0001). OS improvement was consistently observed across prespecified subgroups including ICC option, region, and PD-L1 expression status. In patients with PD-L1 score ≥10%, Arm A also demonstrated significant improvement in OS vs Arm B (median OS: 16.8 vs 10.0 months, HR 0.61 [95% CI 0.44, 0.85], p=0.0017). A significant improvement in PFS was observed in Arm A vs Arm B (median PFS: 7.3 vs 5.6 months; HR 0.62 [95% CI 0.52, 0.75], p<0.0001). Arm A was associated with a higher ORR (63.5% vs 42.4%, odds ratio 2.38 [95% CI 1.73, 3.27], p<0.0001) and more durable response (median DoR: 7.1 [95% CI 6.1, 8.1] vs 5.7 months [95% CI 4.4, 7.1]) than Arm B. Overall, similar proportions of patients in Arms A and B had ≥1 treatment-related treatment-emergent adverse event (TRAE; 96.6% and 96.3%), ≥Grade 3 TRAEs (66.7% vs 64.5%), and TRAEs leading to death (1.9% vs 1.2%), respectively. Serious TRAEs occurred in 28.7% vs 19.3%, and treatment-emergent AEs leading to discontinuation occurred in 31.8% vs 22.4% in Arms A vs B. No new safety signal for tislelizumab was observed. Tislelizumab plus chemotherapy as first-line treatment demonstrated a statistically significant and clinically meaningful improvement in OS over placebo plus chemotherapy in patients with advanced or metastatic ESCC, with a manageable safety profile.